Simulation modeling to assess performance of integrated healthcare systems: Literature review to characterize the field and visual aid to guide model selection.
The guiding principle of many health care reforms is to overcome fragmentation of service delivery and work towards integrated healthcare systems. Even though the value of integration is well recognized, capturing its drivers and its impact as part of health system performance assessment is challenging. The main reason is that current assessment tools only insufficiently capture the complexity of integrated systems, resulting in poor impact estimations of the actions taken towards the 'Triple Aim'. We describe the unique nature of simulation modeling to consider key health reform aspects: system complexity, optimization of actions, and long-term assessments. How can the use and uptake of simulation models be characterized in the field of performance assessment of integrated healthcare systems? A systematic search was conducted between 2000 and 2018, in 5 academic databases (ACM D. Library, CINAHL, IEEE Xplore, PubMed, Web of Science) complemented with grey literature from Google Scholar. Studies using simulation models with system thinking to assess system performance in topics relevant to integrated healthcare were selected for revision. After screening 2274 articles, 30 were selected for analysis. Five modeling techniques were characterized, across four application areas in healthcare. Complexity was defined in nine aspects, embedded distinctively in each modeling technique. 'What if?' & 'How to?' scenarios were identified as methods for system optimization. The mean time frame for performance assessments was 18 years. Simulation models can evaluate system performance emphasizing the complex relations between components, understanding the system's adaptability to change in short or long-term assessments. These advantages position them as a useful tool for complementing performance assessment of integrated healthcare systems in their pursuit of the 'Triple Aim'. Besides literacy in modeling techniques, accurate model selection is facilitated after identification and prioritization of the complexities that rule system performance. For this purpose, a tool for selecting the most appropriate simulation modeling techniques was developed.


Matrix metalloproteinase gene mutations and bioinformatics of telocytes in hepatocellular carcinoma.
Telocytes (TCs) have crucial functions to promote the metastasis of hepatocellular carcinoma (HCC) by over-expressing matrix metalloproteinases (MMPs), but the mechanism by which TCs secrete MMPs in the genome is still unknown. We first cultured and isolated primary TCs from distinct liver cancer tissues and hepatic hemangioma surrounding tissues (Control group). Their whole exon genes were tested by Illumina HiSeq family of platforms and by high-throughput sequencing as well as variant mutations. Moreover, immunohistochemistry, Western blot, and quantitative reverse transcription-polymerase chain reaction assays were utilized to assess the expression of MMPs. The perniciousness of signal-nucleotide polymorphism (SNP) mutations of proteins were predicted by the Polyphen-2 database. Divergent expression and overall survival (OS) of MMPs was screened by StarBase-Pan Cancer plate; and MMPs associated signaling pathways were found by Kyoto Encyclopedia Genes and Genomes. The "competing endogenous RNA (ceRNA)" network was constructed by Cytoscape software. We found that 12 specific types of SNP mutations related to 5 types of MMPs occurred in TCs of liver malignant tumors as a potential result of MMP1, MMP9, and MMP17 overexpression. High levels of MMP1, MMP7, and MMP9 represented poor OS in HCC, and an interactive network of MMPs is shown. Allele shifts of C/T (rs20544) and G/C (rs2250889) in MMP9 were risk factors for TCs in HCC by the prediction of the Polyphen-2 Database. (MMP9 (-3 C/T)) mutation might be a genetic mechanism of upregulating MMP9 in TCs.


Electron microscopy of bundled flagella of the curly mutant of Salmonella abortivoequina.
Mitani, Michiko (National Institute of Genetics, Mishima, Japan), and Tetsuo Iino. Electron microscopy of bundled flagella of the curly mutant of Salmonella abortivoequina. J. Bacteriol. 90:1096-1101. 1965.-The arrangement of flagella was observed by dark-field and electron microscopy in three strains of Salmonella abortivoequina, namely, normal flagellar, curly flagellar, and paralyzed curly flagellar strains. With dark-field microscopy, bundled flagella could be seen in 5 to 10% of actively moving normal or curly mutant cells. Under the electron microscope, a great many bundled flagella were observed in the curly mutant strain, but in the normal strain most of the flagella were dissociated or the bundles were rather loose and irregular. Normal flagella seem to separate easily during the process of preparation, but not the curly ones. Single flagella were found to run parallel with each other and to form a bundle consisting of five or more flagella; the bundle was spirally gyrating, with the characteristic flagellar wave. It is thought that the bundle observed with the electron microscope corresponds to that observed under the dark-field microscope. Further, the marked decrease of bundle formation in the paralyzed curly mutant cells suggests that bundle formation is not caused by curly flagellar structure per se, but corresponds to the mode of locomotion of peritrichously flagellated bacteria.


The primary immune response in mice. I. The enhancement and suppression of hemolysin production by a bacterial endotoxin.
The manner in which a single injection of S. typhosa endotoxin effects the primary hemolysin response to sheep erythrocytes in the mouse has been shown to depend on the dosage, route, and time of administration of the endotoxin, as well as on the route employed for the injection of antigen. The normal production of antibody, following an intravenous or an intraperitoneal injection of red blood cells, is suppressed if the bacterial lipopolysaccharide is given before and by the same route as the antigen. The response to an intraperitoneal injection of sheep red cells is also inhibited if preceded by an intravenous injection of endotoxin. By contrast, hemolysin formation to intravenous antigen is enhanced considerably by a previous intraperitoneal injection of endotoxin, and the response both to intravenous and to intraperitoneal injections of the antigen increases if the endotoxin is given by the same route either simultaneously or shortly after the foreign red cells. These findings are discussed in regard to the physiological action of bacterial endotoxins and the early events in antibody formation.


Cdc42 activation state affects its localization and protein levels in fission yeast.
Rho GTPases control polarized cell growth and are well-known regulators of exocytic and endocytic processes. Cdc42 is an essential GTPase, conserved from yeast to humans, that is critical for cell polarization. Cdc42 is negatively regulated by the GTPase-activating proteins (GAPs) and the GDP dissociation inhibitors (GDIs), and positively regulated by guanine nucleotide exchange factors (GEFs). Cdc42 GTPase can be found in a GTP- or GDP-bound state, which determines the ability to bind downstream effector proteins and activate signalling pathways. Only GTP-bound Cdc42 is active. In this study we have analysed the localization of the different nucleotide-bound states of Cdc42 in Schizosaccharomyces pombe: the wild-type Cdc42 protein that cycles between an active and inactive form, the Cdc42G12V form that is permanently bound to GTP and the Cdc42T17N form that is constitutively inactive. Our results indicate that Cdc42 localizes to several membrane compartments in the cell and this localization is mediated by its C-terminal prenylation. Constitutively active Cdc42 localizes mainly to the plasma membrane and concentrates at the growing tips where it is considerably less dynamic than wild-type or GDP-bound Cdc42. Additionally we show that the activation state of Cdc42 also participates in the regulation of its protein levels mediated by endocytosis and by the exocyst complex.


Stabilized NMR structure of human parathyroid hormone(1-34).
The structure of the biologically-active N-terminal region of human parathyroid hormone, PTH(1-34), was investigated in the presence of 10% trifluoroethanol using two-dimensional proton NMR spectroscopy, distance geometry and dynamic simulated annealing. Complete assignments of all backbone and side chain hydrogens were made with the aid of totally correlated spectroscopy (TOCSY) experiments, providing through-bond 1H-1H connectivities, and NOESY providing through-space and sequential backbone connectivities. Distance and angle constraints were used in the distance geometry algorithm DIANA II to generate a family of structures satisfying all inputs. The lowest energy structures were further refined using the dynamic-simulated-annealing protocol XPLOR 3. The major structural features evident in 10% trifluoroethanol are two segments of alpha-helix extending from residues Glu4 to Lys14/His14 and Ser17 to Asp30. A short length of unordered structure joined the two spans of helix. The structures of the N-terminal regions (4-13/14) agreed closely with the structure found in human parathyroid-hormone-related protein (PTHrP)(1-34) obtained earlier by Ray, Barden and Kemp [19]. However, PTHrP(16-19) exhibited a reverse turn which is incorporated in an extended helix in PTH. The consequent interactions between several hydrophobic residues in the C-terminal region in PTHrP are absent in PTH. Moreover, the turn in PTHrP(22-25) at the start of the C-terminal helix is present as a more standard loop of helix in PTH. Comparisons between the structures of the two hormones has enabled the probable location and structure of the PTH receptor-binding site to be placed in the segment of amphiphilic alpha-helix (24-31).


Ultrasound-guided percutaneous boiling carboplatin injection (PBCI) for the treatment of small hepatocellular carcinoma: a preliminary study.
To evaluate the therapeutic efficacy of ultrasound-guided percutaneous injection of boiling carboplatin (PBCI) for small hepatocellular carcinoma (HCC). PBCI was used to treat 34 HCC patients with 57 tumor nodules less than 3cm in diameter. Thirty-two of them (94.1%) were recurrent cases, including postoperative recurrence in 28, recurrence after percutaneous microwave coagulation therapy in 2 and recurrence after transcatheter arterial chemoembolization in 2. The remaining 2 had an initially treated HCC. Two sessions of PBCI were administered within 1 week for each tumor nodule. Its influences on liver function and blood cell count were monitored. Local recurrence rate, incidence of distant recurrence and survival rate were calculated by Kaplan-Meier method and their influencing factors were analyzed. Patients had a mean follow-up time of 12.7 +/- 5.4 months (from 3 to 22 months). Amount of boiling carboplatin solution (5mg/mL) injected per session ranged from 3mL to 35mL (10.9 +/- 6.9mL), and the total amount used in the two-session course ranged from 6mL to 65mL (21.8 +/- 13.4mL). Of 57 tumor nodules treated with two-session PBCI, technical success was achieved in 53 (93.0%). The cumulative local recurrence rate at 3, 6, 12, 18 months was 3.5%, 7.3%, 16.2% and 16.2%, respectively, with a mean local recurrence-free time of 19.4 +/- 0.8 months. Eighteen out of 34 patients (52.9%) developed distant recurrence, with a mean interval time to distant recurrence of 11.6 +/- 1.4 months. Incidence of distant recurrence at 6, 12, 18 months was 34.1%, 53.2% and 64.5%, respectively. The 1-year and 1.5-year survival rates were 78.3% and 64.2%, respectively, with a mean survival time of 17.8 +/- 1.1 months. Of 28 postoperative recurrent patients, PBCI markedly prolonged the mean postoperative tumor-free survival time from 21.1 +/- 3.4 months to 36.2 +/- 4.7 months (p<0.01). Univariate analysis demonstrated that patients with Child-Pugh grade A liver function had a significantly longer survival time and greater survival rate than those with grade B and C (p<0.05). There were no remarkable changes in liver function and complete blood cell count after PBCI and no major complications were observed. PBCI represented as an effective and safe percutaneous injection therapy for small HCC. It needed only two sessions for the vast majority of HCC less than 3cm in diameter and thus had the advantage of being much less invasive.


Nuances between sedentary behavior and physical inactivity: cardiometabolic effects and cardiovascular risk.
The aim of this study was to highlight the differences between the cardiometabolic effects and the cardiovascular risk of physical inactivity and sedentary behavior. A narrative bibliographic review was conducted. In the research, national and international articles were selected from the PubMed, SciELO, and LILACS databases using the descriptors "sedentary lifestyle, cardiovascular risk, physical inactivity, sedentary behavior, and cardiovascular risks." Both physical inactivity and sedentary behavior are related to metabolic and organic changes, promoting a chronic proinflammatory state, cardiac remodeling, increased body adiposity, and skeletal muscle dysfunction. It is possibly stated that both of them result in a higher risk of developing chronic diseases, resulting in higher global and cardiovascular morbidity and mortality, with nuances in their intrinsic effects. It is inferred that both physical inactivity and sedentary behavior are cardiovascular risk factors that can be modified with the correct clinical approach. It is necessary to differentiate physically inactive individuals from those with a high number of sedentary behaviors. These concepts need better clinical applicability to improve the prevention of primary and secondary cardiovascular risks.


Standard and novel therapeutic approaches to Behçet's disease.
Behçet's disease (BD), a systemic inflammatory disorder of unknown aetiology, is characterised by recurrent attacks of oral aphthous ulcers, genital ulcers, skin lesions, uveitis or other manifestations affecting the blood vessels, gastrointestinal tract, and respiratory and central nervous systems. Although the treatment of BD is empirical, in recent years, it has been shown that early and effective treatment of acute inflammatory lesions and prevention of relapses can help to reduce the disease burden and improve outcome. Randomised, controlled trials are limited in BD, but those that have been conducted have documented favourable effects of colchicine, ciclosporin, azathioprine, thalidomide, dapsone, depot methylprednisolone, rebamipide, sucralfate, benzathine benzylpenicillin, interferon-alpha-2a and etanercept for various BD manifestations. Anti-inflammatory and/or immunosuppressive treatments should be tailored according to the disease severity and prognostic factors. More potent drugs, such as azathioprine, ciclosporin, interferon-alpha and infliximab, are effective in the suppression of more severe systemic features as well as mucocutaneous manifestations of BD. Although no randomised, controlled trials are yet available, results of open studies with both interferon-alpha and infliximab are promising for those patients with disease resistant to conventional immunosuppressive treatments. Multicentre, multi-disciplinary and long-term trials aiming to assess the efficacy of interventions in both the treatment of acute inflammatory attacks and the prevention of relapses are required in order to provide more generalisable results that can lead to better management plans.


The heterogenic tumor microenvironment of hepatocellular carcinoma and prognostic analysis based on tumor neo-vessels, macrophages and α-SMA.
The present study was performed to quantify tumor neo-vessels, macrophages and fibroblasts in the tumor microenvironment of hepatocellular carcinoma (HCC) and explore the prognostic factors of HCC. The distribution of tumor neo-vessels, macrophages and fibroblasts was quantified by immunohistochemistry and inverted microscopy with the CRi Nuance multispectral imaging system, and the correlation of these parameters with the clinico-pathological characteristics and overall survival of the patients was analyzed. The number of tumor neo-vessels and macrophages, and density of the fibroblasts, as calculated by the thickness of the tumor stroma in the tumor microenvironment, ranged from 51-429 (median, 218), 110-555 (median, 259) and 35.6-555.5 µm (median, 247.0), respectively. Using the median values as a cutoff, the cases were stratified into high- and low-density groups. Survival analysis demonstrated that the high-density groups regarding macrophages (χ2=5.249, P=0.022) and fibroblasts (χ2=18.073, P<0.001) had a significantly shorter disease-free survival (DFS) than the low-density groups. The high-density tumor neo-vessel group had a shorter DFS with a median of 5 months than the low-density group with a median of 7 months; however, there was no statistical significance between these two groups (χ2=1.663, P=0.197). Regarding the above three stromal components combined, all of the cases were classified into low-, middle- and high-density groups. Survival analysis demonstrated that the high-density group of stromal components had a shorter DFS than the other two groups with a median of 3 months (χ2=14.439, P=0.001). Multivariate analysis by Cox regression indicated that cirrhosis, metastasis stage, as well as macrophage and fibroblast density were independent prognostic factors. In conclusion, the key elements in the tumor microenvironment, including tumor neo-vessels, macrophages and fibroblasts, were heterogenic in HCC tissues and have significant roles in HCC invasion and metastasis. Stromal components are associated with the prognosis of patients with HCC; the higher the density of stromal components, the poorer the prognosis of patients with HCC.


[Influence of conjugated linoleic acids on metabolic processes in cells and tissues].
Conjugated linoleic acids (CLA) are constitutional and geometric isomers of this acid. The most commonly consumed geometric isomers are cis-9,trans-11 (c9, t11) CLA and trans-10, cis-12 (t10,c12) CLA. These isomers together with trans-9,trans-11 CLA and trans-10,trans-12 CLA constitute about 90% of all CLA in natural products. Different structure of the isomers affects their functions in the body. Differences in the effects on organs and tissues are sometimes small and sometimes opposed, sometimes the isomers work synergistically. Diverse influence has been shown mainly in neoplastic processes and lipid metabolism. For example, differences in inhibition of proliferation of prostate cancer cells are explained by different pathways: t10,c12 CLA acts on apoptosis and cell cycle control genes, while c9,t11 CLA regulates genes involved in metabolism of arachidonic acid with subsequent impairment of eicosanoids synthesis. Other studies have shown that t10,c12 CLA, but not c9,t11 CLA, can induce fat reduction in adipose tissue and apoptosis of adipocytes in mice.


RAB2A controls MT1-MMP endocytic and E-cadherin polarized Golgi trafficking to promote invasive breast cancer programs.
The mechanisms of tumor cell dissemination and the contribution of membrane trafficking in this process are poorly understood. Through a functional siRNA screening of human RAB GTPases, we found that RAB2A, a protein essential for ER-to-Golgi transport, is critical in promoting proteolytic activity and 3D invasiveness of breast cancer (BC) cell lines. Remarkably, RAB2A is amplified and elevated in human BC and is a powerful and independent predictor of disease recurrence in BC patients. Mechanistically, RAB2A acts at two independent trafficking steps. Firstly, by interacting with VPS39, a key component of the late endosomal HOPS complex, it controls post-endocytic trafficking of membrane-bound MT1-MMP, an essential metalloprotease for matrix remodeling and invasion. Secondly, it further regulates Golgi transport of E-cadherin, ultimately controlling junctional stability, cell compaction, and tumor invasiveness. Thus, RAB2A is a novel trafficking determinant essential for regulation of a mesenchymal invasive program of BC dissemination.


Primary Bacterial Pyomyositis in Children: A Systematic Review.
Tropical pyomyositis has had a recent increase in the United States, Europe, and other nontropical areas. The purpose of this study was to provide an accurate description of the demographics, presenting features, sites of involvement, microbiology, imaging modalities, medical and surgical management, complications, and predictors of clinical course. We searched PubMed, Cochrane, Web of Science Collection, Scopus, and Embase databases yielding 156 studies. Of these, 23 articles were selected for statistical analysis. The average age at presentation was 8.4±1.9 years with males more commonly affected. Fever, painful limp, and localized pain were the most common presenting symptoms. Pelvis, lower extremity, trunk and spine, in descending order, were the most commonly affected locations. Iliopsoas, obturator musculature, and gluteus musculature were the most commonly affected muscle groups. The mean time to diagnosis was 6.6±3.05 days. Staphylococcus aureus was the most common offending organism. The mean length of hospital stay was 12.0±4.6 days. Medical management alone was successful in 40% of cases (143/361) with an average duration of 9.5±4.0 and 22.7±7.2 days of intravenous and oral antibiotics, respectively. Surgical management consisted of open drainage in 91.3% (199/218) or percutaneous drainage in 8.7% (19/218) of cases. Painful limp, fever, and larger values of white cell count and erythrocyte sedimentation rate were associated with an increased need for surgery. Obturator and calf muscle involvement were strongly associated with multifocal involvement. There were 42 complications in 41 patients (11.3%). Methicillin-resistant S. aureus was associated with an increased risk of complications. The most common complications were osteomyelitis, septicemia, and septic arthritis. Primary pyomyositis should be considered in cases suggesting pediatric infection. Magnetic resonance imaging is the most commonly used imaging modality; however, ultrasound is useful given its accessibility and low cost. Medical management alone can be successful, but surgical treatment is often needed. The prognosis is favorable. Early diagnosis, appropriate medical management, and potential surgical drainage are required for effective treatment. Level IV-systematic review.


[Evaluation of breast cancer treatment at a tertiary-level institution with Popular Health Insurance in Mexico].
In our country breast cancer represents a major health problem. Only 45% of all population has access to health services, the consequence is delay in diagnosis and treatment. In Mexico, 66% of all new cases of breast cancer are diagnosed in locally advanced stages. From May 2007 the Health System Protection Against Catastrophic Expenses, called Seguro Popular (SP), breast cancer was included in covering the treatment of this neoplasm in any patient without access to social security. To evaluate the results and impact of SP in the adjuvant and neoadjuvant treatment of a group of patients diagnosed with breast cancer at an institution of national reference. We analyzed a group of 259 patients in stages (I-IIIC). The clinical stages I and II (55 patients) were treated with adjuvant chemotherapy FAC -T (fluorouracil 500 mg/m2, adriamycin 50 mg/m2 and cyclophosphamide 500 mg/m2 (FAC) followed by 12 weeks of paclitaxel 80 mg/m2 +/- trastuzumab loading dose of 4 mg/kg followed by 2 mg/kg); 204 patients in locally advanced stages (IIB-IIIC) received FAC-T +/- trastuzumab followed by surgery. Adjuvant treatment consisted of endocrine therapy for hormone-sensitive patients and radiotherapy 50 cGy according to international standards. The age at diagnosis was 47 years (range 23-68). 80% of them were locally advanced stages (IIB-IIIC) and were treated in a neoadjuvant setting, 20% was in early stages, treated with surgery and adjuvant chemotherapy The disease-free survival and overall survival at 30 months was 85.7 and 90% respectively. Overall pathologic complete response was obtained in 15% of cases. In the subgroup analysis showed that 41% of patients HER2 (+), 29% of triple-negative patients and 9% of hormone-sensitive tumors achieved complete pathological response (p = 0.0001). This is the first analysis of efficacy of adjuvant and neoadjuvant treatment in breast cancer since the introduction of popular secure non-entitled population. It is clear that treatment efficacy is similar to that reported in the literature, with 15% of pRC and survival to 30 months in 94-80%. The coverage of health expenditures treats a larger number of patients optimally. Along with this, efforts should be made to reduce the high frequency of diagnosis at advanced stage.


Severe sepsis from a Ciprofloxacin resistant salmonellosis in a kidney transplant recipient.
Salmonellosis is a relatively rare complication in kidney transplant recipients that cannot be clinically distinguished from other forms of enteritis. Among kidney transplant patients, it varies broadly in intensity, and is highly associated with extra-intestinal disease, bacteremia, and, in this case, a high mortality rate. Here we describe a clinical case of ciprofloxacin resistant salmonellosis in a kidney transplant patient. This case illustrates how immunosuppressed patients can be exposed to rare forms of infection, often clinically difficult to identify, and possibly with severe clinical courses and poor outcomes despite evidence-based empiric antibiotic therapy.


Rhinomaxillary phycomycosis: report of case.
A case of rhinomaxillary phycomycosis has been reported. Although the occurrence of the phycomycetes-type of infection is relatively rare, the oral and maxillofacial surgeon should be alert for debilitated patients, especially uncontrolled diabetics, who may show the incipient signs and symptoms of this opportunistic fungal disease.


Covid-19 Front-Liners: Experiences of Palliative Care Providers in a Tertiary Hospital.
In "normal" times, palliative care (PC) service delivery is confronted with many challenges thereby making access to care difficult. Now, we are in the era of COVID-19 where the healthcare ecology is radically changed. During this process of radical transformation, there are some ramification of COVID-19 on PC service delivery. Yet, there is a paucity of empirical evidence to support this claim. We explored PC providers' perspectives on delivering PC services in the era of COVID-19. Using an exploratory descriptive qualitative approach, we conducted face-to-face and telephone interviews with seven PC service providers at Korle Bu Teaching Hospital, Ghana. Haase's adaptation of Colaizzi's method was employed as the analysis strategy. Two main themes emerged: ramifications and adaptations. The ramifications of COVID-19 on PC service delivery included changes in care relationship, perceived increased responsibilities, psychological distress, shortage of medicines, and treatment delays. In an attempt to mitigate the challenges posed by COVID-19 on PC service delivery, the following mechanisms adaptations were made: halting of service provision, resorting to tele-consultation, adopting shift system and reducing number of appointments, and adoption of infection prevention and control strategies. Our results indicate that COVID-19 has substantial ramification of PC service delivery. In conclusion, priority should be given to the training of healthcare workers on emergency preparedness for future pandemics. Also, continuous professional development would be needed in order build PC service providers' skills and capacity to effectively utilize tele-consultation in PC service delivery.


Effect of tyrosine kinase inhibitors on clathrin-coated pit recruitment and internalization of epidermal growth factor receptor.
Several inhibitors of epidermal growth factor receptor (EGFR) kinase and Src family kinases (SFK) were employed to study the role of these kinases in EGFR internalization through clathrin-coated pits. The EGFR kinase-specific compound PD158780 substantially diminished EGFR internalization. PP2, an inhibitor of SFK, had a moderate effect on EGFR internalization in several types of cells, including cells lacking SFK, indicating that the inhibition of endocytosis by PP2 is mediated by kinases other than SFK. In contrast, SU6656, a more specific inhibitor of SFK, did not affect EGFR internalization. To examine what stage of internalization requires receptor kinase activity, we established a quantitative assay based on three-dimensional fluorescence microscopy that measures co-localization of an EGF-rhodamine conjugate and a fluorescently tagged clathrin adaptor protein complex, AP-2. Interestingly, recruitment of EGFR into coated pits did not require physiological temperature because the maximal accumulation of EGFR in coated pits was observed at 4 degrees C. Pretreatment of the cells with PD158780 prevented EGFR recruitment into coated pits, whereas the inhibitor did not block the internalization of receptors that had first been allowed to enter the coated pits at 4 degrees C. These data demonstrate that the activation of receptor kinase is essential for the initial, coated pit recruitment step of endocytosis.


Can one do good medical ethics without principles?
The criteria for determining what it is to do good medical ethics are the quality of ethical analysis and ethical justifications for decisions and actions. Justifications for decisions and actions rely on ethical principles, be they the 'famous four' or subsidiary ethical principles relevant to specific contexts. Examples from clinical ethics, research ethics and public health ethics reveal that even when not stated explicitly, principles are involved in ethical justifications. Principles may come into conflict, however, and the resolution of an ethical dilemma requires providing good reasons for preferring one principle over another.


Compare the safety and efficacy of endoscopic third ventriculostomy and ventriculoperitoneal shunt placement in infants and children with hydrocephalus: a systematic review and meta-analysis.
Endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt placement are two surgical options used for treatment of non-communicating hydrocephalus. The purpose of this study was to compare the efficiency and safety of these techniques in pediatric patients. An extensive literature review regarding the clinical outcome, safety, and efficiency of ETV and shunting in treatment of hydrocephalus was conducted in Medline, PubMed, Cochrane, and Google Scholar databases up to November 27th, 2015. Patient demographics, ETV and shunting success and failure rates were extracted. A total of 7 two-arm studies were included for quantitative analysis and 25 single-arm studies were included for systematic review. The two-arm studies recruited a total of 6995 patients: 1046 in the ETV group and 5949 in the shunt group. The pooled results showed that the 1 year success rate of ETV and shunt-placement procedure were similar (pooled RR = 0.870, 95% CI = 0.680 to 1.112, P = 0.266). The failure rate in the ETV treatment group was 0.9 times higher than in the shunt group; however, the results did not reach statistical significance (pooled RR = 0.893, 95% CI = 0.576 to 1.383, P = 0.611). Both ETV and shunts are associated with similar 1 year success and failure rates. Therefore, there are no current indications to recommend one mode of treatment over the other. Future studies designed to assess the effectiveness of ETV and shunt procedures depending on patient's age and etiology are warranted.


Brain and spinal cord levels of histamine in Lewis rats with acute experimental autoimmune encephalomyelitis.
Acute experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by inoculation with guinea pig spinal cord homogenate emulsified with Mycobacterium tuberculosis-enriched complete Freund's adjuvant (CFA). Control rats were inoculated with CFA alone. Control and EAE rats were killed on days 7, 9, 11, and 13 postinoculation, and regional brain and spinal cord levels of histamine were determined. No regional differences in histamine content between control and EAE rats were seen on day 7 or 9 postinoculation. However, depending on the region, EAE rats exhibited significantly higher levels of histamine in their CNS on day 11 or 13 postinoculation or on both. Thus, regionally and temporally specific increases in brain and spinal cord levels of histamine develop concomitant with or just after the appearance (on day 10 postinoculation) of clinical signs of acute EAE, a finding suggesting that histamine may be involved in the development or expression of acute EAE in Lewis rats.


The Effect of Peer Support on Foot Care in Patients with Type 2 Diabetes.
Diabetes mellitus is one of the prevalent diseases in the world with several complications including diabetic foot ulcers. The aim of this study was to investigate the effect of peer support on foot care in patients with type 2 diabetes. This clinical trial study was performed at selected centers of Isfahan University of Medical Sciences in 2017. Fifty patients with type 2 diabetes were randomly assigned into intervention and control groups. Five 30-min. supportive training sessions were held for the intervention group by the peers and during 35 days. Foot Care Confidence/Foot-Care Behavior Scale For Diabetes (FCCS-FCB) was completed by both groups before, immediately after and 1 month after the intervention. Collected data were analyzed using Chi-square, Mann-Whitney, repeated measures ANOVA and t-test. : Mean (SD) age of subjects was 56.46 (7.36) years old Mean (SD) score of self-efficacy (F2, 26 = 54.71, p < 0.001), preventive behaviors (F2, 26 = 28.46, p < 0.001), and potentially damaging (F2, 26 = 27.89, p < 0.001) had significant differences between the two groups immediately and 1 month after the peer support. Peer support can enhance foot care behaviors in diabetic patients. Therefore, using people who are successful in the education and support of patients has a significant role, and nurses can use them as a support in the field of care and follow-up. However, health agencies are responsible for providing the patients with the best guidelines, and these results can be useful as an evidence for them.


Influence of the incommensurability in Sr14-xCaxCu24O41 Family Compounds.
We study the influence of the structural modulation on the low energy physics of the Sr14-xCaxCu24O41 oxides, using ab initio determination of the on-site and nearest-neighbor effective parameters. The structural modulations appear to be the key degree of freedom responsible for the low energy properties, such as the electron localization, the formation of dimers in the x=0 compound, or the antiferromagnetic order in the x=13.6 compound.


Epigenetic control of gene expression: Potential implications for cancer treatment.
Epigenetic changes are defined as inherited modifications that are not present in DNA sequence. Gene expression is regulated at various levels and not only in response to DNA modifications. Examples of epigenetic control are DNA methylation, histone deacetylation and mi-RNA expression. Methylation of several tumor suppressor gene promoters is responsible for their silencing and thus potentially sustain cancerogenesis. Similarly, histone deacetylation can lead to oncogene activation. mi-RNA are small (18-20 nucleotides) non-coding RNA fragments capable of inhibiting other m-RNA, ultimately altering the balance in oncogene and tumor suppressor gene expression. It has been shown that growth of several tumor types can be stimulated by epigenetic changes in various phases of cancerogenesis, and drugs able to interfere with these mechanisms can have a positive impact on tumor progression. As matter of fact, epigenetic changes are dynamic and can be reversed by epigenetic inhibitors. Recently, methyltransferase and histone deacetylase inhibitors have attracted the attention of researchers and clinicians as they potentially provide alternative therapeutic options in some cancers. Drugs that inhibit DNA methylation or histone deacetylation have been studied for the reactivation of tumor suppressor genes and repression of cancer cell growth. Epigenetic inhibitors work alone or in combination with other therapeutic agents. To date, a number of epigenetic inhibitors have been approved for cancer treatment. The main challenge in the field of epigenetic inhibitors is their lack of specificity. In this review article we describe their mechanisms of action and potential in cancer treatment.


Fragment-based approaches in drug discovery and chemical biology.
Fragment-based approaches to finding novel small molecules that bind to proteins are now firmly established in drug discovery and chemical biology. Initially developed primarily in a few centers in the biotech and pharma industry, this methodology has now been adopted widely in both the pharmaceutical industry and academia. After the initial success with kinase targets, the versatility of this approach has now expanded to a broad range of different protein classes. Herein we describe recent fragment-based approaches to a wide range of target types, including Hsp90, β-secretase, and allosteric sites in human immunodeficiency virus protease and fanesyl pyrophosphate synthase. The role of fragment-based approaches in an academic research environment is also examined with an emphasis on neglected diseases such as tuberculosis. The development of a fragment library, the fragment screening process, and the subsequent fragment hit elaboration will be discussed using examples from the literature.